Greater thari 10% of hurhahs suffer chronic sleep disorders, hut the genetic m[unreadable]:hanisims that regulate sleep are largely unknown. The identification of defective Hypocretin/Orexin i[Hcrt) signaling as a cause of narcolepsy provided ia genetic enUry point into sleepresearch.but an effective treatment for this disorder has not yet been found. Moreover, only a sniall fraction of sleep disorders are associated with narcolepsy, indicating that additional genes that control sleep and wakefulness remain to be identified. The objective of this proposal is to use zebrafish as a simpile and cost-effective vertebrate rnodel system to study the genetics of Hcrt Jsighaling andsleep. Zebrafish are an excellent model for these studies because they are amenable to high-throughput genetic screens and, unlike invertebra:tes, have a Hcrt ortholog and the basic brain stl-iictures that regulate sleepin mammals. I have shown that Hcrt overexpression causes an insomhia-like phenotype in zebrafish larvae. In Specific Aim 1,1 will use pharmacological agents to determine the genetic and neurologic mechanisms by which Hcrt dverexpress;ion induces this phenotype^ These experiments vvill use reagents identified in a small molecule screen that I performed during the K99 phase of this grant. The results of these experiments will improve understanding Of Hcrt function and may provide cIue:S to the basis of chronic insomnia. In Specific Aim 2,1 will study secreted peptides that caused specific sleep phenotypes in the genetic overexpression screen that I performed during the K99 phase of this grant. These experiments vyill confirm results frorh the screen and characterize potentially novel genetic mechanisms that regulate sleep. My long-term career goalis to elucidate: the genetic and neurologic mechanisms that regulate sleep/wake states, with the hope that this knowledge will lead to treatments for sleep disorders. Caltech is an excellent environnient to pursue this goal since there are several labs performing outstanding research in the genetics of behavior arid behavioral neuroscience, as well as labs studying the regulation of sleep in other model systems.